Scott A. Beers

Phosphatase inhibitors—III. Benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase

Further investigation of the structural requirements of a series of benzylphosphonic acid inhibitors of human prostatic acid phosphatase has led to the highly potent series of alpha-aminobenzylphosphonic acids. The alpha-benzylaminobenzylphosphonic acid, with an IC50 = 4 nM, exhibited a 3500-fold improvement in potency over the carbon analogue, alpha-phenylethyl. The enhanced potency may be due to a combination of four favorable interactions including those with the phosphate binding region, the presence the hydrophobic moieties of the benzylamino and phenylphosphonic acid, and a rigid conformer produced by an internal salt bridge between the phosphonate and the alpha-amino group. Replacement of the phosphonic acid moiety with a phosphinic or carboxylic acid as well as deletion of the benzyl substitution of the alpha-amino group led to great reductions in potency.

Novel hydroxyphosphonate inhibitors of CD-45 tyrosine phosphatase

CD-45 tyrosine phosphatase [E.C. 3.1.3.48] is an important player in the regulation of cell activation and proliferation in hematopoetic cells. As part of a program in immune response modulation, we prepared the first series of small organic molecule inhibitors of CD-45. The preparation and in vitro screening of these hydroxyphosphonates is described herein.

1-Naphthylmethylphosphonic acid derivatives as osteoclastic acid phosphatase inhibitors

Abstract Inhibition of the enzyme, osteoclastic acid phosphatase (OAP) may be a viable approach to the treatment of osteoporosis. A series of arylmethylphosphonic acids were synthesized and shown to be inhibitors of OAP. The most potent inhibitor, bis -benzoyl-1-naphthylmethylphosphonic acid (7a) had an IC50 = 1.4 μM.

Anti-AIDS agents. 291. Anti-HIV activity of modified podophyllotoxin derivatives

Abstract Podophyllotoxin derivatives containing structural modifications at C-4 and in the methylenedioxy A-ring, lactone D-ring, and phenyl E-ring have been tested for inhibition of HIV replication. The four most promising compounds (6, 7, 8, and 19), with the methylenedioxy A-ring opened and methylated and the 4′-position demethylated, had EC50s less than 0.001 μM and therapeutic indices greater than 120.

N-(5-substituted) thiophene-2-alkylsulfonamides as potent inhibitors of 5-lipoxygenase

Compound 4k N-[5-(4-fluoro)phenoxythien-2-yl]methanesulfonamide is representative of a new class of potent inhibitors of 5-lipoxygenase (5-LO). These versatile compounds exhibit dose-dependent inhibition of 5-LO with IC50s ranging from 20-100 nM in the rat basophilic leukemia (RBL-1) cell homogenate assay and submicromolar IC50s in both the RBL-1 and human peripheral blood leukocyte (PBL) whole cell assays. Compound 4k also showed significant anti-inflammatory activity in the adjuvant arthritic rat at an oral dose of 3 mg/kg.

Benzylphosphonic acid inhibitors of human prostatic acid phosphatase

Abstract A series of α-substituted benzylphosphonic acids is described as inhibitors of human prostatic acid phosphatase, an enzyme which has been used as a model to study aryl phosphatases. The most potent inhibitors in this series are 2-trifluoromethylbenzhydrylphosphonic acid (9 μM), and α-(2-phenylethyl)benzylphosphonic acid (14 μM). The structure-activity studies suggest that bulk tolerance beyond the phosphate binding area limits the steric or hydrophobic contribution to inhibitor potency achieved through α-carbon substitution.